Ibuprofen containing hard shell capsules

Abstract

The present invention relates to pharmaceutically acceptable and stable compositions, which are preferably clear transparent, for liquid filling hard shell capsules, hard shell capsules containing these compositions, and a process for preparing these hard shell capsules and whereby the shells of said hard capsules are preferably clear transparent.

1. A pharmaceutically acceptable composition in the form of a solution for a liquid filling for a hard shell capsule comprising, based upon the total weight of the composition,
 a) from 35 to 75% by weight of a racemic mixture of ibuprofen, 
 b) from 0.2 to 0.35 mole equivalents of an alkali hydroxide selected from the group consisting of sodium hydroxide and potassium hydroxide per mole of ibuprofen, 
 c) from 40 to 55% by weight of an emulsifier which is a polyoxyethylene castor oil derivative and d) from 12 to 18% weight of a medium chain triglyceride, having a density in the range of 0.85–1.1 at 60 degrees C. and selected from the group consisting of 
 (i) a polyoxoethylene alkyl ether selected from the group consisting of polyoxyl 2 cetyl ether, polyoxyl 10 cetyl ether, polyoxyl 20 cetyl ether, polyoxyl 4 lauryl ether, polyoxyl 23 lauryl ether, polyoxyl 2 oleyl ether, polyoxyl 10 oleyl ether, polyoxyl 20 oleyl ether, polyoxyl 2 stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 2 stearyl ether, polyoxyul 10 stearyl ether, polyoxyl 20 stearyl ether, polyoxyl 100 stearyl ether polyoxyl 20 cetostearyl ether and mixtures thereof; 
 (ii) a propylene glycol ester selected from the group consisting of propylene glycol dicocoate, propylene glycol distearate, propylene glycol dioctanoate, propylene glycol dipelargonate, propylene glycol diundecanoate, propylene glycol monostearate, propylene glycol monohydroxystearate, propylene glycol monolaurate, propylene glycol monomyristate, propylene glycol monooleate and mixtures thereof; 
 (iii) a glyceryl ester selected from the group consisting of glyceryl monooleate, glyceryl monostearate, glyceryl palmitosterate and mixtures thereof; 
 (iv) a sorbitan ester selected from the group consisting of sorbitan di-isostearate, sorbitan dioleate, sorbitan monolaurate, sorbitan monoisosterate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesqui isostearate, sorbitan tri-isostearate, sorbitan trioleate, sorbitan tristearate and mixtures thereof; 
 (v) a polyoxyethylene castor oil derivative selected from the group consisting of polyoxy 5 castor oil, polyoxy 9 castor oil, polyoxy 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil and mixtures thereof; 
 (vi) a polyoxyethylene sorbitan fatty ester selected from the group consisting of polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, polysorbate 120 and mixtures thereof; 
 (vii) a polyoxyethylene stearate selected from the group consisting of polyoxyl 6 stearate, polyoxyl 8 stearate, polyoxyl 12 stearate, polyoxyl 20 stearate and mixtures thereof; and mixtures of (i)–(vii),] and 
 
       wherein the viscosity of the composition is in the range of 1000–4000 cps at 25 degrees C. 
     
     
       2. A pharmaceutical composition according to  claim 1 , wherein the emulsifier c) is polyoxyl 35 castor oil or polyoxyl 40 hydrogenated castor oil. 
     
     
       3. A pharmaceutical composition according to  claim 2 , wherein the emulsifier c) is contained in an amount from 45 to 50% by weight. 
     
     
       4. A pharmaceutical composition according to  claim 1 , wherein the emulsifier c) is a mixture of polyoxyl 35 castor oil or polyoxyl 40 hydrogenated castor oil and which composition additionally comprises caprylic/capric triglyceride. 
     
     
       5. A liquid filled pharmaceutical hard capsule containing a composition in the form of a solution which comprises, based upon the total weight of the composition,
 a) from 35 to 75% by weight of a racemic mixture of ibuprofen, 
 b) from 0.2 to 0.35 mole equivalents of an alkali hydroxide selected from the group consisting of sodium hydroxide and potassium hydroxide per mole of ibuprofen, 
 c) from 40 to 55% by weight of an emulsifier which is a polyoxyethylene castor oil derivative and d) from 12 to 18% by weight of a medium chain triglyceride, having a density in the range of 0.85–1.1 at 60 degrees C. and selected from the group consisting of 
 (i) a polyoxoethylene alkyl ether selected from the group consisting of polyoxyl 2 cetyl ether, polyoxyl 10 cetyl ether, polyoxyl 20 cetyl ether, polyoxyl 4 lauryl ether, polyoxyl 23 lauryl ether, polyoxyl 2 oleyl ether, polyoxyl 10 oleyl ether, polyoxyl 20 oleyl ether, polyoxyl 2 stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 2 stearyl ether, polyoxyul 10 stearyl ether, polyoxyl 20 stearyl ether, polyoxyl 100 stearyl ether polyoxyl 20 cetostearyl ether and mixtures thereof 
 (ii) a propylene glycol ester selected from the group consisting of propylene glycol dicocoate, propylene glycol distearate, propylene glycol dioctanoate, propylene glycol dipelargonate, propylene glycol diundecanoate, propylene glycol monostearate, propylene glycol monohydroxystearate, propylene glycol monolaurate, propylene glycol monomyristate, propylene glycol monooleate and mixtures thereof; 
 (iii) a glyceryl ester selected from the group consisting of glyceryl monooleate, glyceryl monostearate, glyceryl palmitosterate and mixtures thereof; 
 (iv) a sorbitan ester selected from the group consisting of sorbitan di-isostearate, sorbitan dioleate, sorbitan monolaurate, sorbitan monoisosterate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquiisostearate, sorbitan tri-isostearate, sorbitan trioleate, sorbitan tristearate and mixtures thereof 
 (v) a polyoxyethylene castor oil derivative selected from the group consisting of polyoxy 5 castor oil, polyoxy 9 castor oil, polyoxy 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil and mixtures thereof; 
 (vi) a polyoxyethylene sorbitan fatty ester selected from the group consisting of polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, polysorbate 120 and mixtures thereof; 
 (vii) a polyoxyethylene stearate selected from the group consisting of polyoxyl 6 stearate, polyoxyl 8 stearate, polyoxyl 12 stearate, polyoxyl 20 stearate and mixtures thereof; 
 
       and mixtures of (i)–(vii),] and 
       wherein the viscosity of the composition is in the range of 1000–4000 cps at 25 degrees C. 
     
     
       6. A liquid filled pharmaceutical hard capsule containing a composition according to  claim 3 . 
     
     
       7. A liquid filled pharmaceutical hard capsule containing a composition according to  claim 1 . 
     
     
       8. A composition according to any one of  claims 2 ,  3  and  4  wherein the viscosity of the composition is in the range of 1200–2500 cps at 25 degrees C. 
     
     
       9. A liquid filled pharmaceutical hard capsule according to any one of  claims 5 – 7  wherein the capsule is clear and transparent and the composition contained therein is in the form of a solution of ibuprofen.